X-dioxo-j



Patented Aug. 17, 1937 2,090,068

UNITED STATES PATENT OFFICE 2,4-DIOXO-3,3-DIALKYL-TETRAHYDRO PYRIDINESAND PROCESS FOR THE MANUFACTURE OF SAME Ernst Preiswerk, Munchenstein,near Base], and Otto Schnider, Basel, Switzerland, assignors toHoffmann-La Roche Inc., Nutley, N. J., a corporation of New Jersey NoDrawing. Application June 1, 1936, Serial No. 82,992. In Germany June17, 1935 8 Claims. (01. 260-42) Ketones react with formic esters to formhyprecipitated unchanged from the alkaline solu- Qr y-methy1eneket0nes.Dl l yl i tion with acid or even with carbon dioxide. By the estersreact in a similar manner (Berichte der a ti n of methylating agents,compounds meth- Deutschen Chemischen Gesellschaft vol. 59, 1926, ylatedon the nitrogen atom may be obtained,

page 110) Hydrogenation yields the corresponding piper- 5kyl-tetra-hydro-pyridines, is obtained by heattetra-hydrO-pynqme formsmjystanme s.ta ing hydroxy-methylene-dialkyl-aceto-acetic esblecompounds 1'phemfbzfi-dlmethyl 4'lsq' ters with ammonia to a highertemperature. The Wlth 10 conversion is performed in two phases.methy1'4'dlmethyl'ammo'pyrazolone' At first the amino-methylene compoundis pronew compounds are to be used a medl' duced according to theequation cines, as they exert a strong soponfic action.

The amino-methylene compounds of the dialkyl- Example 1 aceto-aceticesters are stable. They may be purified by distillation under reducedpressure. 1100 Pa ts by Weight o yd s t lu ne are Whereas the formationof the amino-methylp ed Ov r 3 parts by Weight of finely ground enecompounds of the dialkyl-aceto-acetic esters d m- A m 'e Of 100 par s byWeig o takes place rapidly even at room temperature methyl form te and136 p s y Weight f dior only slightly above, ring-closure in theabethy1ace 0-ac s r i r pp d in at 2030 sence of other condensing agentsthan ammonia C. while stirring. After some time the sodium only sets inat about 100 C. or above. It could Salt of the hydroxy-methylenecompound begins 25 not be foreseen that the carboxy group of the to beprecipitated. When all the sodium has redialkyl-aceto-acetic estercompound would conacted the product is poured into ice and after itdense with the amino group, because it is a known has settled theaqueous layer is separated from fact that for instancediethyl-aceto-acetic ester the toluene. By acidifying the aqueoussoludoes not react with ammonia (Annalen der tion thehydroxy-methylene-diethyl-aceto-acetic 3O Chemie vol. 231, 1885, page244). The transester is precipitated as an oil. It may be puriformationof the amino-methylene-dialkyl--acetofied by distillation in vacuo.acetic esters into the corresponding pyridine 214 parts by weight ofhydroxy-methylene-ditakes place with particular ease if a strongerethyl-aceto-acetic ester are dissolved in 400 parts condensing agentthan ammonia, for instance by weight of 5% aqueous ammonia. Thereacsodium-alcoholate or the like, is used; alkalis, tion product iswarmed slightly and the precipsuch as potassium hydroxide, may also beused itated oil is collected. The amino-methyleneto advantage. Thisinternal condensation may dialkyl-aceto-acetic ester thus obtained maybe be illustrated by the following formula: purified by distillationunder reduced pressure. 0 CH=OH 40 R1 R1 6 5 NH:CH=CHCO O/COOR+NH 1 4OO+ROH R, R1 and R2 represent alkyl groups, R. represents It forms aviscous oil boiling at 1'79-182 C./14 principally ethyl or methyl; R1and R2 likewise mm. represent alkyl groups which may be the same To analcoholic sodium-ethylate solution, preor difierent, saturated orunsaturated. pared with 23 parts by weight of sodium and .The,2,4-dieing-2 3 dialkyl tetra hydro pyri- 260 parts by weight of absolutealcohol, 213 parts di nes are readily, soluble in o rganic "solvents. byeight 7 of ,amino methylene -diethyl aceto- They dissolve ilut a ka hy ri id en e-ester ar de e h 'br d t a e i forming a tw llow.s lbti l 19KPl= 9lliim iefi103 ???F FQi PWi n F-Q W 5 by it is kept gently boiling.It is then left to cool and the alcohol is distilled off in vacuoascompletely as possible. The solid residue is dissolved in ice Water andneutralized with dilute hydrochloric acid. The precipitated solid crudeproduct is separated from the liquid by filtration and purified bydistillation in vacuo (B. Pt.

187-189" C./14 nun.) and by crystallization from benzene with anaddition of petroleum ether.

The 2,4-dioxo-3,3-diethyl-tetra-hydro-pyridine forms colourless crystalsmelting at 98-99 C., which are easily soluble in warm water, slightlysoluble in cold water. The compound is very easily soluble in the usualorganic solvents except in petroleum ether. By catalytic hydrogenationthe corresponding piperidine derivative is obtained. With pyrazolonederivatives well crystalline stable compounds inmolecular proportionsare formed, for instance with 1-phenyl-2,3-dimethyl-.4-dimethylamino-pyrazolone (M. P.=69'70 C.) or with1phenyl-2,3-dimethyl4-isopropyl-pyrazolone (M. 1?;93" ,C.)

Example 2 238; parts by weight of hydroxy-methylene-diallyl-aceto-aceticester (obtained from diallylaceto-acetic ester and formic ester) aredissolved in 500 parts by weight of methanol; 70 parts by weight ofdried ammonia are passed in while cooling with ice. The solution is thenheated in a closed receptacle for 6 hours to 150 C. After cooling thesolvent and the excess of ammonia are removed by distillation. Theremaining reactionproduct may be purified in the manner described inExample 1 for the diethyl compound.

The 2,4-dioxo-3,3-dially1-tetra-hydro pyridine thus obtained melts at8l82 C. and boils under 14 mm. pressure at' .208210-C. withoutdecomposition.

. Example 3 242 parts by weight of hydroxy-methylenedipropyl-aceto-acetic ester (B. Pt. 135-137" C./14 mm.) are dissolvedin. 250 parts by weight of absolute alcohol; 20 parts by weight ofammonia gas are passed into the solution while cooling. After Warming togentle ebullition 280 parts by weight of an alcoholic sodium-ethylatesolution corresponding to 23 parts by weight of sodium are added and toensure a complete conversion the productis further heated for half anhour under a reflux condenser to boiling point. The solvent is thencompletely removed by distillation under reduced pressure. When cold theresidue is dissolved in 500 parts by weight of ice-cold water and thereaction product precipitated by acidifying with dilute hydrochloricacid. For complete purification the residue may after drying berecrystallized from petroleum ether.

The2,4-dioxo-3 3-dipropyl-tetra-hydro-pyridine forms colourless needlesmelting at 92-93 C. By methylating it is transformed into 1-methyl-2,4-dioxo3,3-di-n-propyl-tetra-hydro-pyridine melting at 61-62 C.

Example 4 186 parts by weight of diethyl-aceto-acetic ester arecondensed with formic ester in the manner described in Example "1. 5 Tothe aqueous solution of the sodium salt of the hydroxy-methylene com-,poundseparated from the toluene, "70 parts by weight'ofammoniumchloride are added and the product heated for an hour to -'85 C. Theprecipitated amino methylene diethyl acetoacetic ester is diluted withether,"separ,ated from the aqueous solution and the solvent removed 'bytoluene; B. Pt. 129-133 (1/14 distillation. Then the residue isdissolved in 250 parts by weight of alcohol and parts by weight of 50%aqueous potassium hydroxide solution are added to the solution, thetemperature of the solution being kept at 50 C. for a quarter of anhour. To obtain the reaction-product the alcohol is removed bydistillation under reduced pressure, the residue dissolved in cold waterand acidified with dilute sulphuric acid. The product is identi cal withthe product of Example 1.

, Example 5 ing to 23 parts by weight of sodium are added and thealcohol isremoved by distillation. When cold the residue is dissolved in600 parts by weight of cold water and carbon dioxide passed in until theprecipitation is completed. If before the treatment with carbon dioxidethe alkaline solution has been filtered, will be almost pure. petroleumether the 2,4-dioXo-3,3-'n-butylnpropyl-tetra-hydro-pyridine is obtainedin colourless crystals melting at 101-102 C.

Example 6 the precipitated product 242 parts by weight ofhydroxy-methylene-npassed in 20 part b" weight of ammonia gas, thesolution is heated for half an hour to .-5060f.;C. Then a, solution ofsodium ethylate, prepared from 23 parts by weight of sodium and 260parts By recrystallization from parts by weight of alcoholicsodium-ethylate solution correspondy -ethyl-aceto-acetic ester aredissolved in 400 rts by weight of absolute alcoh Aft a ng by weight ofabsolute alcohol, is added and the J.

reaction-product boiled for a short time under a reflux condenser. Theproduct is worked-up in the manner described in Example 3, The 2,4-

dioxo 3,3 n butyl ethyl-tetra-hydro-pyridine melts at 86 C.

Example 7 20 parts by weight of ammonia gas are passed into anice-cooled solution of 242 parts by weight ofhydroxy-methylene-isopropyl-n-propyl-acetoacetic ester (prepared withsodium from isopropyln-propyl-aceto-acetic ester and'formic ester inmm.) in 320 parts by weight of methanol. The solution is heated until itbegins to boil. 'Then a solution of 60 partsby Weight of potassiumhydroxide in 240 parts by weight of methanol is added and the productheated for 30 minutes under a reflux condenser until. it begins to boil.After evaporating the solvent the potassium salt obtained is dissolvedin cold water and the2,4-dioxo-3,3-isopropyl-n-propyl-tetra-hydro-pyridine is precipitatedfrom the solution with acids. When recrystallized from dilute alcohol,the compound melts at -131-'132 C.

Example 8 ammonia-and sodium-ethylate in the manner described in Example6. i

The pure compound thus-obtainedmelts"at C. V

We claim:

1. The 2,4-dioxo-3,3-dia1kyl-tetra-hydro-pyridines of the type formula:

R (EH 9M H I\ on a 2 00 R being unsubstituted in the 5 and 6 positions,and in which R. and R" are alkyl groups.

2. The 2,4-dioxo-3,3-dietYhyl-tetra-hydro-pyridine, forming colourlesscrystals melting at 98-99 (3., being easily soluble in warm water,slightly soluble in cold water, very easily soluble in the usual organicsolvents except petroleum ether, forming well crystalline stablecompounds with pyrazolone derivatives:

3. The amino-methylene-dialkyl-aceto-acetic esters.

4. The amino-methylene-diethyl-aceto-acetic ester.

5. The process for the manufacture of 2,4-dioxo 3,3 dialkyltetra-hydro-pyridines, which consists in treatingamino-methylene-dialkylaceto-acetic esters, obtained by the action ofammonia on hydroxy methylene dialkyl acetoacetic esters, with alkalinecondensing agents.

6. The process for the manufacture of 2,4- dioxo 3,3dialkyl-tetra-hydro-pyridines, which consists in treatingamino-methylene-dialkylaceto-acetic esters, obtained by the action ofammonia on hydroxy methylene dialkyl acetoacetic esters, with alkalinecondensing agents in alcoholic solution.

7. The process for the manufacture of 2,4- dioxo-3,3-diethyl-tetra hydropyridine, which consists in treating amino-methylene-diethylaceto-aceticester, obtained by the action of ammonia on hydroxy methylene diethylacetoacetic ester, with alkaline condensing agents.

8. The process for the manufacture of 2,4- dioxo 3,3diethyl-tetra-hydro-pyridine, which consists in treatingamino-methylene-diethylaceto-acetic ester, obtained by the action ofammonia on hydroxy methylene diethyl-acetoacetic ester, with alkalinecondensing agents in alcoholic solution.

ERNST PREISWERK. OTTO SCHNIDER.

